Method and device for intradermally delivering a substance

ABSTRACT

A device for delivering a substance into the skin of a patient includes a body and a skin penetrating device having at least one skin penetrating member, such as a microneedle. The body includes an internal cavity and a device for indicating the delivery of a sufficient amount of the substance to the patient and for producing a dispensing pressure to dispense and deliver the substance from the cavity. The indicating device is visible from the exterior of the delivery device. In some embodiments, the indicating device is an elastic expandable diaphragm which, when the cavity is filled with a substance, creates the dispensing pressure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 10/112,933 filed Apr. 2,2002, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a method and device for deliveringa substance intradermally to a patient. The invention is also directedto a microneedle delivery device for containing and delivering a unitdose of a substance intradermally to a patient.

BACKGROUND OF THE INVENTION

Subcutaneous delivery devices using a cannula are effective for manyapplications. However, the pain normally induced by the cannula hasprompted the development of less painful delivery methods. Recently, anumber of intradermal devices employing microneedles have been designed.The microneedles have a length selected to penetrate the skin to a depthwhere a drug or pharmaceutical agent can be delivered to a patient.

In humans, the skin is made up of several layers, with the uppercomposite layer being the epithelial layer. The outermost layer of theskin, the stratum corneum, has well known barrier properties to preventmolecules and various substances from entering the body and analytesfrom exiting the body. Bouwstra, et al., (2001) Skin Pharmacol Appl SkinPhysiol, 14 Suppl 1:52-62.

The stratum corneum is a complex structure of compacted keratinized cellremnants having a thickness of about 10-30 microns which forms awaterproof membrane to protect the body from invasion by varioussubstances and from the outward migration of various compounds.

The natural impermeability of the stratum corneum prevents theadministration of most pharmaceutical agents and other substancesthrough the skin. Numerous methods and devices have been proposed toenhance the permeability of the skin and to increase the diffusion ofvarious drugs through the skin to be utilized by the body. Typically,increasing either the permeability of the skin or the force or energyused to drive therapeutics through the skin enhances delivery of drugsthrough the skin. Bouwstra, et al., supra.

Another method of delivering various substances through the skin is byforming micropores or microcuts through the stratum corneum. Bypenetrating or piercing the stratum corneum and delivering a drug to theskin in or below the stratum corneum, many drugs can be administeredeffectively. The devices for piercing the stratum corneum generallyinclude a plurality of micron-sized needles or blades having a lengthselected to pierce the stratum corneum without passing completelythrough the epidermis. Examples of these devices are disclosed in U.S.Pat. No. 5,879,326 to Godshall et al., U.S. Pat. No. 5,250,023 to Lee etal., and WO 97/48440.

The above-noted devices that include micron-sized needles or bladesdeliver the substances to the body by allowing the substances to flowthrough pores or channels in the device. Many of these prior devices donot provide a controlled delivery of a substance to the patient.

The prior methods and devices for the intradermal administration ofsubstances have exhibited limited success. Accordingly, a continuingneed exists for an improved device for administration of various drugsand other substances to the body.

SUMMARY OF THE INVENTION

The present invention is directed to a method and device for thedelivery of a substance though the skin of a patient. More particularly,the invention is directed to a method and device for delivering apharmaceutical agent, such as a drug or vaccine, below the stratumcorneum of the skin to a depth at which the pharmaceutical agent can beabsorbed and utilized by the body. The invention is further directed toa method of manufacturing and assembling a device for intradermallydelivering a substance through the skin of a patient.

Accordingly, a primary object of the invention is to provide a lowprofile device to provide an increased comfort level to the patient,wherein the device has a skin penetrating member for introducing thesubstance to the patient.

A further object of the invention is to provide a device for penetratingthe skin for delivering a unit dose of a substance through the skinsubstantially without pain to the patient.

Another object of the invention is to provide a device having at leastone micro skin penetrator, (e.g., microtube, microneedle, microblade orlancet) for piercing the stratum corneum of the skin to deliver asubstance to a patient.

A further object of the invention is to provide a delivery device havingat least one skin penetrating member and a chamber for containing asubstance to be delivered to a patient.

Still another object of the invention is to provide an intradermaldelivery device having an indicator for indicating that a sufficientamount of a substance, for example, a premeasured dose, has beendelivered from a chamber intradermally to a patient and an arrangementfor producing a dispensing enhancing pressure in the chamber throughoutthe dispensing operation.

Another object of the invention is to provide a device for delivering asubstance to a patient, wherein the device has a support with aninternal supply channel having a very low dead volume and a micro skinpenetrator device bonded to the support in fluid communication with thesupply channel for delivering the substance to the patient.

A further object of the invention is to provide a delivery device havinga plurality of micro skin penetrating members, wherein the deviceincludes at least one elastic wall for producing a dispensing enhancingpressure in an internal chamber containing a substance to deliver to thepatient and for indicating when a sufficient amount of the substance hasbeen dispensed.

Another object of the invention is to provide an intradermal deliverydevice having an internal chamber with an arrangement for filling andpressurizing the internal chamber.

Another object of the invention is to provide for the intradermaldelivery device a liquid source for supplying a liquid substance to theinternal cavity by a force sufficient to pressurize the housing andproduce the dispensing enhancing pressure throughout the dispensingoperation.

A yet further object of the invention is to provide a method forintradermally delivering a substance to a patient comprising providing adelivery device which has a housing with an internal cavity and at leastone skin penetrating device in fluid communication with the cavity,wherein the housing is pressurizable for maintaining a dispensingenhancing pressure in the cavity, the delivery device is positioned on atarget area on the skin of a patient, and sufficient force is applied tocause the skin penetrating device to penetrate the skin of the patient.A substance is introduced into the cavity of the housing, the substanceproducing the dispensing enhancing pressure in the cavity.

These and other objects of the invention are substantially achieved byproviding an intradermal delivery device comprising a housing having aninternal cavity dimensioned to receive a substance for delivery to apatient, a skin penetrating device in fluid communication with thecavity, and a resiliently biased movable member in fluid communicationwith the cavity. The resiliently biased movable member produces adispensing enhancing pressure in the cavity for dispensing the substancefrom the cavity to the skin penetrating member and indicates thedelivery of a sufficient amount of the substance to the patient.

The objects and advantages of the invention are further attained byproviding an intradermal delivery device comprising a housing having atleast a portion made of an expandable material with sufficientelasticity to produce a dispensing enhancing pressure when the cavity isfilled with a substance and to indicate that the cavity has not yetdelivered a sufficient amount of the substance. A skin penetratingdevice is coupled to the housing and is in fluid communication with thecavity.

The present invention is directed to a device for delivering a substanceinto the skin of a patient. More particularly, the invention is directedto an intradermal delivery device and to a method for administering asubstance below the stratum corneum of the skin of a patient where thesubstance is absorbed and utilized by the body.

As used herein, the term “penetrate” refers to entering an object, suchas a layer of the skin, without passing completely through. The term“pierce” refers to passing completely through an object, such as a layerof the skin.

The device and method of the present invention are suitable for use inadministering various substances, including pharmaceutical agents, to apatient, and particularly to a human patient. As the term is usedherein, a pharmaceutical agent includes a substance having biologicalactivity that can be delivered through the body membranes and surfaces,particularly the skin. Examples of pharmaceutical agents includeantibiotics, antiviral agents, analgesics, anesthetics, anorexics,antiarthritics, antidepressants, antihistamines, anti-inflammatoryagents, antineoplastic agents, vaccines, including DNA vaccines, and thelike. Other substances that can be delivered intradermally to a patientinclude proteins, peptides and fragments thereof. The proteins andpeptides can be naturally occurring, synthesized or recombinantlyproduced.

The delivery device of the present invention is constructed forpenetrating selected layers of the dermis of a patient to attain thedesired depth of penetration. The desired depth of penetration isdetermined by the substance being delivered and the desired rate ofabsorption by the body. Less penetration speeds the uptake of thesubstance by the body, and greater penetration slows delivery. It iscontemplated that the skin penetrating member has a length of about 50microns to about 1,500 microns. It is also contemplated that an array ofsuch skin penetrating members can be used. The penetrating members havea length designed to pierce the stratum corneum without inducing pain byimpacting nerve endings. By delivering a substance below the stratumcorneum, the substance can be absorbed and utilized by the bodysubstantially without pain or discomfort to the patient. Preferably, theskin penetrating members have a length and diameter to penetrate theskin to a depth where the patient experiences little or no pain, forexample, below the stratum corneum and above the nerve endings.

The present invention is directed to an intradermal delivery device fordelivering a substance into the skin of a patient where the device isable to maintain a dispensing enhancing pressure for delivering thesubstance. More particularly, the invention is directed to a unit dosedelivery device for the sustained delivery of a substance through theskin of a patient.

The objects, advantages and other salient features of the invention willbecome apparent from the following detailed description which, taken inconjunction with the annexed drawings, discloses preferred embodimentsof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following is a brief description of the drawings:

FIG. 1 is a top view of a delivery device in accordance with a firstembodiment of the invention;

FIG. 2 is a front elevational view of the device of FIG. 1;

FIG. 3 is a bottom view of the device of FIG. 1, showing a skinpenetrating device;

FIG. 4 is an enlarged partial cross-sectional view of the device of FIG.2, showing the skin penetrating device 3 bonded to a housing;

FIG. 5 is an enlarged cross-sectional view taken along the line 5-5 inFIG. 1, showing a cavity in the housing and a diaphragm in a normal,relaxed state;

FIG. 6 is a cross-sectional view similar to FIG. 5 but showing thecavity filled with a substance and the diaphragm in a stretched statefor producing an indication of an insufficient amount dispensed and adispensing enhancing pressure;

FIG. 7A is a cross-sectional side view of a delivery device inaccordance with a second embodiment of the invention, wherein the devicehas an expandable diaphragm forming a top wall;

FIG. 7B is a top view of the device of FIG. 7A;

FIG. 8 is a cross-sectional side view similar to FIG. 7A but with thecavity filled with a substance and the diaphragm in the stretched state;

FIG. 9 is a top view of a delivery device in accordance with a thirdembodiment of the invention showing an inlet port and an expandablediaphragm in a top wall;

FIG. 10 is a bottom view of the delivery device of FIG. 9;

FIG. 11 is an enlarged cross-sectional view taken alone the line 11-11in FIG. 9;

FIG. 12 is a top view of a delivery device in accordance with a fourthembodiment of the invention, showing an expandable top wall and an inletport coupled to a side of a housing;

FIG. 13 is a bottom view of the device of FIG. 12, showing a microneedlearray; and

FIG. 14 is an enlarged cross-sectional view taken along the line 14-14in FIG. 12, showing a microneedle array and an internal chamber.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As can be seen from FIGS. 1-6, a first embodiment of a delivery deviceaccording to the present invention, which is designated generally by thereference numeral 10, comprises a housing 12 and a skin penetratingdevice 14. Housing 12 is dimensioned to contain a substance to bedelivered to a patient and to be removably attached to the surface ofthe skin. Skin penetrating device 14 is associated with housing 12 topenetrate the skin of the patient and deliver the substance from housing12 through the skin penetrating device 14. The present invention hasboth human and veterinary applications in delivering therapeutics acrossthe stratum corneum. For example, canine and feline dermatology issimilar to human dermatology with respect to the location andpermeability of strata corneum. Moriello, K. A.; Mason, I. S., Handbookof Small Animal Dermatology, Pergamon, 1995, pp. 19-44.

The housing 12 has a substantially circular configuration, with a topwall 16, a bottom wall 18 and a side wall 20 extending between top wall16 and bottom wall 18. Top wall 16, bottom wall 18 and side wall 20define an internal cavity 22 of housing 12, as is shown in FIGS. 5 and6.

Bottom wall 18 is substantially flat and is defined in part by the skinpenetrating device 14, the bottom wall having a peripheral portion 23,including a central opening 24 for receiving skin penetrating device 14.The peripheral portion 23 of the bottom wall 18 surrounding opening 24defines a ledge 26 extending beyond a receiving side wall 28, the ledge26 and the receiving side wall 28 being dimensioned to receive skinpenetrating device 14.

The skin penetrating device 14 of the embodiment illustrated in FIGS.1-6 has a microneedle array. As can best be seen from FIG. 4, skinpenetrating device 14 includes a base 30 having a substantially planartop face 32 and a bottom face 34. A plurality of spaced-apart skinpenetrating members 36 in the form of microneedles extend downwardlyfrom bottom face 34. As is shown in FIGS. 4 and 5, the skin penetratingmembers 36 have a generally cylindrical side wall 38 and a beveled tip40. An axial passage 42 extends through each of the skin penetratingmembers 36 from its beveled tip 40 to the top face 32 of the base 30.Axial passages 42 are in fluid communication with cavity 22 of housing12. Typically, skin penetrating members 36 extend perpendicularly frombottom face 34 and are arranged in an array formed by spaced-apart rowsand columns.

In a preferred embodiment of the invention, skin penetrating device 14is coupled to bottom wall 18 of housing 12 so that bottom face 34 of thebase 30 is in the same plane as the bottom surface of bottom wall 18 ofhousing 12. In other words, bottom face 34 of skin penetrating device 14is flush with bottom wall 18 of housing 12. As is shown in FIG. 4,opening 24 in bottom wall 18 is slightly larger than the outer peripheryof skin penetrating device 14 to define a small gap between the outerperiphery of the skin penetrating device and the receiving side wall 28.Typically, skin penetrating device 14 is attached to bottom wall 18 byapplying an adhesive 46 to fill the gap. Preferably, adhesive 46, whichhas a viscosity permitting the adhesive to flow around gap 44, can becured to permanently couple skin penetrating device 14 to housing 12.

As can be seen from FIG. 3, skin penetrating device 14 has asubstantially square base 30 that is centrally located in bottom wall 18of housing 12. In alternative embodiments, base 30 of skin penetratingdevice 14 can have a generally circular shape or other shape. In asimilar manner, circular is just one suitable shape for housing 12.Alternatively, housing 12 can have a substantially square or otherrectangular shape or still other shape.

In preferred embodiments, housing 12 is pressurizable, the housingincluding a resiliently biased dispensing member 48 for indicating thata sufficient amount of a substance has been delivered from the cavity 22to a patient and for providing a dispensing enhancing pressure to boostthe delivery rate of the substance throughout the dispensing operation.The resiliently biased dispensing member 48 moves to a position in whicha sufficient amount of the substance has been delivered, the presence ofthe member 48 in that position indicating that a sufficient amount ofthe substance has been delivered. In view of its indicating function,the resiliently biased dispensing member 48 is visible from the exteriorof the delivery device 10. The top wall 16 has a generally concave innerface 50, a substantially convex outer face 52, and an arrangement forfilling cavity 22 with a substance to be delivered to a patient. In theillustrated embodiment, the arrangement comprises a coupling member 54having an inlet port 56 defining a passage in the coupling member 54 anda check valve 58 to allow a substance to be directed into cavity 22while preventing leakage of the substance from cavity 22 out throughinlet port 56. As an alternative, the arrangement can comprise a septumthat is pierceable by, for example, the needle of a syringe, the septumbeing capable of resealing itself upon removal of the needle. Otherarrangements can be used.

The resiliently biased dispensing member 48 is a resilient expandablemember coupled to top wall 16 to close an opening 60 in the top wall. Inpreferred embodiments of the invention, the resiliently biasedexpandable dispensing member 48 is a diaphragm made from an elastomericmaterial that stretches when cavity 22 is filled under pressure andreturns to its normal shape and dimension as the pressure is relieved.The elastomeric material has an area, thickness, and elasticity toprovide a dispensing pressure sufficient to dispense a substance fromcavity 22 through skin penetrating device 14 and into the patient. Inmoving from its pressurized position to its unpressurized position, theresiliently biased dispensing member 48 moves through a volume that isequal to the volume of the cavity 22 when the resiliently biased memberis in its unpressurized position.

In the embodiment illustrated, the resiliently biased dispensing member48 has a generally circular shape and is coupled to top wall 16. Inalternative embodiments, the resiliently biased dispensing member 48 canhave other shapes and dimensions depending on the dispensingrequirements of device 10. In addition, dispensing member 48 can becoupled to a side wall. Examples of suitable materials for thedispensing member 48 are natural rubber and synthetic rubbers, such aspolystyrene butadiene copolymers. The resiliently member 48 can be aseparate member that is attached to housing 12 by a suitable adhesive,or it can be integrally formed with housing 12 the housing 12 and member48 by molding as a single piece. Housing 12 is made from a rigidnon-expanding material.

Device 10 is dimensioned to be applied directly to the surface of theskin of the patient in a manner such that skin penetrating device 14penetrates the skin to the desired depth. The device 10 includes aflexible strip material 64 extending from opposite sides of housing 12.Strip material 64 is preferably a flexible polymeric film having anadhesive 66 on bottom face 68. Strip material 64 has a width slightlyless than the diameter of housing 12 and a length sufficient to securehousing 12 to the surface of the skin of a patient. Typically, adhesive66 is a pressure sensitive adhesive.

Device 10 is preferably constructed as a single use disposable item thatcan be made by a number of processes. Housing 12 is typically made froma polymeric material by suitable injection, vacuum or blow moldingprocesses. In the embodiment illustrated, top wall 16, bottom wall 18and side wall 20 are formed in one piece. As an alternative, housing 12can be assembled from separate elements bonded together by an adhesiveto form a fluidtight housing.

Typically, device 10 is manufactured and packaged in sterile conditions.The device 10 can be filled immediately prior to use with the substanceto be administered, or it can be pre-filled. A cover can be applied overskin penetrating device 14 to protect the skin penetrating members andmaintain the skin penetrating device in a sterile condition duringstorage. A suitable release sheet (not shown) is typically provided onadhesive layer 66. The release sheet and the cover can be removedimmediately prior to use.

A method for delivering a substance intradermally to a patient usingdevice 10 can be appreciated from FIG. 6. Device 10 is placed againstthe surface of the skin 70 of a patient and pressed downwardly againstthe skin until skin penetrating members 36 penetrate the skin. The depthof penetration is determined by the length, width and spacing of skinpenetrating members 36. Insufficient spacing between skin penetratingmembers 36 causes increased skin resistance to the penetration of theskin penetrating members, a phenomenon sometimes called the “bed ofnails” effect because some performers use it to enable them to lie on ahazardous looking bed of nails with no significant injury. Preferably,skin penetrating members 36 have a dimension and orientation topenetrate the surface of skin 70 substantially uniformly, as is shown inFIG. 6. In the embodiment illustrated, ends of the strip material 64 arecoupled to the side wall 20 of the device 10 in an area spaced a slightdistance from bottom wall 18 of housing 12. This arrangement maintains aslight downward pressure of housing 12 on skin 70 when strip material 64is attached to skin 70, as is shown in FIG. 6. Alternatively, stripmaterial 64 can be coupled to the side wall 20 at the bottom wall 18.

As can be appreciated from FIGS. 5 and 6, coupling member 54 isconstructed to couple with a unit dose delivery device 72. For thispurpose, coupling member 54 can include a Luer-type collar or a frictionfit type coupling. The illustrated unit dose delivery device 72 includesan outer housing 74, a hinged actuating member 76 and a dispensing tip78 having a Luer-type connector or other construction for mating withcoupling member 54 in a fluid tight manner as shown in FIG. 6. Unit dosedelivery device 72 also includes an internal bladder (not shown) influid communication with dispensing tip 78. By the use of the unit dosedelivery device 72, the device 10 can be filled with a premeasured doseof a substance to be delivered to a patient. As a result, theresiliently biased member 48 again reaching its unexpanded orunpressurized position indicates that a premeasured dose has beendelivered. One suitable unit dose delivery device is commerciallyavailable from Becton Dickinson Company under the trademark UNIJECT.Other unit dose delivery devices can be used instead.

Device 10 is positioned on the skin 70 of the patient, as can be seenfrom FIG. 6, and unit dose delivery device 72 is coupled to couplingmember 54. Actuating member 76 is pressed inwardly to compress theinternal bladder of the unit dose delivery device 72 and inject thesubstance contained in the bladder into cavity 22 of housing 12, asindicated by arrows 80 in FIG. 6. The substance is injected withsufficient force to expand the resiliently biased member 48 outwardlyfrom top wall 16. Unit dose dispensing device 72 is then removed fromcoupling member 54, while check valve 58 prevents the escape of thesubstance from the device 10 through coupling 56. The elasticity of theresiliently biased member 48 maintains a dispensing enhancing pressurein cavity 22 to force the substance slowly through the axial passages 42of skin penetrating members 36 into the skin of a patient where thesubstance can be utilized by the body.

The resiliently biased member 48 returns to its original shape anddimension as the substance is dispensed. The dimensions and elasticityof the resiliently biased member 48 determine the volume of substancethat can be delivered and the rate of delivery of the substance to thepatient. After a dose of the substance has been delivered to thepatient, the resiliently biased member 48 has returned to its normalshape and dimension, thereby indicating that a sufficient amount of thesubstance has been delivered. Then the device 10 is removed from theskin of the patient and discarded.

Housing 12 is preferably made from a plastic material that isnon-reactive with the substance being delivered to the patient. Suitableplastic materials include, for example, polyethylene, polypropylene,polyesters, polyamides, polycarbonates, and copolymers thereof.

Skin penetrating device 14 can also be made from materials known in theart to be suitable. The skin penetrating members 36 can be microneedlesformed from a silicon wafer that is machined or etched to form themicroneedle array. As an alternative, the skin penetrating members canbe microneedles formed from any of stainless steel, tungsten steel,alloys of any of nickel, molybdenum, chromium, cobalt and titanium, andother non-reactive metals. As another alternative, the skin penetratingmembers can be microneedles formed from ceramic materials, glass orpolymers. In further embodiments, skin penetrating device 14 can bedefined by distinct skin penetrating members that are mounted in asuitable base.

The skin penetrating members 36 have a length suitable to achieve thedesired depth of penetration in the skin. The length and thickness ofthe skin penetrating members are selected based on the substance beingadministered and the thickness of the skin in the location where thedevice is to be applied. The skin penetrating members can bemicroneedles, microtubes, solid or hollow needles, lancets and the like.Generally, the skin penetrating members 36 have a length of about 50microns to about 1,500 microns, and preferably about 500 microns to1,000 microns. In one embodiment, the skin penetrating members 36comprise needles of about 30-gauge to about 50-gauge needles mounted inapertures formed in a base. The skin penetrating members 36 are fixed tothe base 30, from which they extend outwardly to have an effectivelength of about 50 microns to about 1,500 microns. As an alternative toa circular cross section, the skin penetrating members 36 can have asubstantially square cross-sectional shape. As other alternatives, theskin penetrating members 36 can be triangular, cylindrical, orpyramid-shaped or they can be flat blades.

The array of skin penetrating members 36 has a width and lengthsufficient to contain the number and size of skin penetrating members 36necessary to achieve the desired result for depth of skin penetrationand delivery or sampling rate. Where an array of skin penetratingmembers 36 is used, the area of the array is preferably about 1 cm.sup.2to about 10 cm.sup.2.

Generally, when the device is used as a delivery device, apharmaceutical agent or drug solution is introduced into the port 56 bya syringe or other fluid dispensing device. In alternative embodiments,a dried or lyophilized drug or pharmaceutical agent is provided incavity 22, on the outer surfaces of the skin penetrating members 36, orin the axial passages 42 of the skin penetrating members. A diluent suchas distilled water or saline solution can then be injected into cavity22 to dissolve and reconstitute the drug or pharmaceutical agent. Thedrug or pharmaceutical agent is then delivered to the patient throughmicroneedles.

FIGS. 7A, 7B and 8 show another embodiment of the delivery device 82. Inthis embodiment, the delivery device 82 includes a housing 84 having abottom wall 86 and side walls 88. A skin penetrating device 90 having aplurality of spaced-apart skin penetrating members 91 is coupled tobottom wall 86. A resiliently biased top wall 92 is connected to sidewalls 88 and spaced from bottom wall 86 to define an internal cavity 94.The skin penetrating members 91 can have all the various forms of theskin penetrating members 36 of the previously described embodiment fordelivering the substance to the patient.

The top wall 92 is made from an elastic material that can stretch toenlarge cavity 94 when a substance is introduced into cavity 94 underpressure. As in the previous embodiment, top wall 92 includes a couplingmember 96 having a through passage and an internal check valve, wherebycoupling member 96 can be connected to a unit dose injection device,such as the unit dose injection device 72 shown in FIGS. 5 and 6. Bottomwall 86 and side wall 88 are preferably made from a rigid, non-expandingmaterial.

As in the previous embodiment, the delivery device 82 includes aflexible strip material 100 having an adhesive coating 102. In theembodiment illustrated, strip material 100 is coupled to side walls 88adjacent bottom wall 86 so that the bottom face of strip material 100 isin the same plane as bottom wall 86.

The delivery device 82 is placed on the surface of the skin 106 andpressed downwardly to enable needles 91 of skin penetrating member 90 topenetrate the skin to a selected depth. Strips 100 are attached to skin106 by adhesive 102 to releasably secure device 82 in position. The unitdose injection device is then coupled to coupling 96, and a selecteddosage of a substance is injected into cavity 94 under sufficientpressure to expand top wall 92 outwardly as shown in FIG. 8. Theelasticity of top wall 92 creates a dispensing pressure sufficient todispense the substance through skin penetrating device 90 into the skinwhere the substance can be absorbed and utilized by the body. The returnof the top wall to its unexpanded position indicates that a sufficientamount of the substance has been delivered.

FIGS. 9-11 show another embodiment of a delivery device 110 according tothe invention. The delivery device 110 includes a housing 112 having atop face 114, a bottom face 116 defining a recess 118, and a downwardlyopening internal cavity 120. The recess 118 is defined by a ledge 122and a perimeter wall 124 for receiving a skin penetrating device 126.

Skin penetrating device 126 includes a base 128 having a plurality ofskin penetrating members 130, such as microneedles each having an axialthrough passage, extending outwardly from a bottom face 132 of base 128.Skin penetrating members 130 can be integrally formed with base 128 asin the previous embodiment. Alternatively, the skin penetrating members,130 can be separate elements that are fixed in respective apertures inbase 128. The base 128 has a thickness corresponding to the depth of theperimeter wall 124 so that bottom face 132 of the base is in the sameplane as bottom face 116 of housing 112.

As can be seen from FIGS. 10 and 11, bottom face 116 has an area greaterthan the area of skin penetrating device 126 to provide a marginsurrounding skin penetrating device 126. A pressure sensitive adhesive136 is provided on the margin of bottom face 116 for attaching thedelivery device 110 to the skin of a patient. Preferably, pressuresensitive adhesive 136 defines a continuous closed loop encircling skinpenetrating device 126 and forms a seal around a delivering area on theskin contacted by skin penetrating device 126.

As can be seen from FIGS. 9 and 11, collar 138 having a central passage140 communicating with cavity 120 projects above the top face 114 of thehousing 112. A check valve 142 and a coupling member 144 are provided oncollar 138. An opening 146 in top face 114 is closed by a resilientlybiased member 148 connected to the housing 112 to seal cavity 120. Theexpanded position of the resiliently biased member 148 is indicated bythe dashed lines in FIG. 1. The resiliently biased member 148 ispreferably made from an elastomer capable of stretching and deformingoutwardly from housing 112 and creating an internal dispensing enhancingpressure to helps dispense a substance from cavity 120 through needles130 to the patient.

The delivery device 110 in the embodiment of FIGS. 9-11 has a relativelylow profile and a small internal volume in cavity 120. The smallinternal volume reduces the dead space and minimizes waste of thesubstance that remains in housing 112 after the substance is deliveredto the patient. Typically, housing 112 is made from a polymeric materialthat is sufficiently flexible to conform to the contours of the skin ofthe patient.

The delivery device 110 is placed against the surface of the skin 150 ofa patient and pressed downwardly so that the skin penetrating members130, such as microneedles, penetrate the skin. A substance to bedelivered to the patient is introduced through coupling member 144 andcentral passage 140 into cavity 120 with sufficient pressure to expandthe dispensing member 148 as indicated by the dashed lines in FIG. 11.The substance to be delivered to the patient can be introduced intocavity 120 from a unit dose injection device 72 or 98 as in the previousembodiments, or from a syringe, an infusion pump or other dispensingdevice. The dispensing device is then separated from coupling member 144when a sufficient amount of substance is contained in cavity 120. Thedispensing member 148 creates a dispensing enhancing pressure sufficientto force the substance through the skin penetrating members 130 into theskin of the patient. As the substance is delivered, the dispensingmember 148 moves toward its unexpanded position and, by reaching thatposition, indicates that a sufficient amount of the substance has beendelivered. After the substance has been delivered to the patient, device110 is peeled from the surface of the skin and discarded.

FIGS. 12-14 show another embodiment of a delivery device 152 inaccordance with the invention. The delivery device 152 includes ahousing 154, an expandable dispensing member 156 and a skin penetratingdevice 158.

Housing 154 has a substantially circular configuration with a low flatprofile and a central aperture 160 having a top ledge 162 adjacent a topsurface 164. As is shown in FIG. 14, a resiliently biased member 156 isconnected to top ledge 162 to close a top end of the aperture 160.

Housing 154 also includes a bottom ledge 166 in a bottom face 168surrounding a bottom end of the aperture 160. Bottom ledge 166 defines arecess for receiving and mounting skin penetrating device 158 on housing154. As is shown in FIG. 14, dispensing member 156 and skin penetratingdevice 158 are spaced apart to define with the housing 154 an internalcavity 170.

Housing 154 is provided with a coupling member 172 extending from a sideface 174 of housing 154, in substantially the same plane as housing.Collar 172 includes an inlet port 176 defining an internal axial passageextending to the internal cavity 170, as well as a check valve 178 and acoupling member 180 for coupling with a supply device. The axial passageof the port 176 extends from coupling member 180 through a side 174 ofhousing 154 for communicating with the internal cavity 170.

Bottom face 166 of housing 154 has an area greater than the area of skinpenetrating device 158. A pressure sensitive adhesive forming acontinuous closed loop is applied to a margin 168 of the bottom face,encircling skin penetrating device 158. Preferably, adhesive 182 isapplied to the margin 168 to cover a sufficient surface area to attachdevice 152 to the surface of the skin of a patient.

The resiliently biased member 156 is preferably an expandable membermade from an elastomeric material. In the embodiment illustrated, theresiliently biased member 156 is an elastic diaphragm member 184 thatexpands outwardly from housing 154 when a substance is introduced tocavity 170 under pressure. The elastic properties of diaphragm member184 are sufficient to produce a dispensing enhancing pressure in cavity170.

As in the previous embodiments, skin penetrating device 158 includes abase 186 having a plurality of spaced-apart skin penetrating members188, for example, microneedles. A method of delivering a substanceintradermally to a patient using device 152 appreciated from FIG. 14.The delivery device 152 is placed against the skin 170 of a patient andpressed downwardly so that the skin penetrating members 188 penetratethe skin 190 and the adhesive 182 contacts skin 190 with sufficientforce to attach device 152 to skin and form a continuous seal andbetween the device and the skin, all around skin penetrating device 158.A unit dose injection device, like the injection device 72 is connectedto coupling 180 for introducing a substance into cavity 170 undersufficient pressure to expand the dispensing member 184 outwardly asindicated by the dashed lines in FIG. 14. The unit dose injection deviceis disconnected after cavity 170 is filled. The delivery device 152 isretained in contact with skin 190 for a sufficient time for thedispensing member 184 to dispense the substance from cavity 170 throughthe skin penetrating members 188 and into the skin of the patient. Byagain reaching its unexpanded position, the resiliently biased member156 indicates that a sufficient amount of the substance has beendelivered. The delivery device 152 can then be separated from skin 190and discarded.

While various embodiments have been chosen to illustrate the invention,it will be appreciated by those skilled in the art that variousadditions and modifications can be made to the invention withoutdeparting from the scope of the invention as defined in the appendedclaims.

1. An intradermal delivery device for delivering a substance to a patient, said device comprising: a housing having an internal cavity, said cavity being dimensioned to receive a substance for delivery to a patient; a skin penetrating device in fluid communication with said cavity; and an indicator having an indicating surface responsive to a pressure within said internal cavity, wherein said indicating surface indicates the delivery of a sufficient amount of the substance to the patient, wherein said indicator comprises an indicating member having at least a portion movable to a position in which a sufficient amount of the substance has been delivered, wherein the presence of the indicating member in said position indicates that a sufficient amount of the substance has been delivered and the movable portion of the indicating member is visible from the exterior of the intradermal delivery device when the movable portion is in said position.
 2. The intradermal delivery device of claim 1, wherein said skin penetrating device comprises at least one skin penetrating member having a length of about 500 microns to about 1,000 microns and is a needle from about 30 gauge to about 50 gauge.
 3. The intradermal delivery device of claim 1, wherein said housing further includes an inlet for passing said substance into said cavity.
 4. The intradermal delivery device of claim 3, further comprising a check valve connected to said inlet for preventing the substance from leaving said cavity through said inlet.
 5. The intradermal delivery device of claim 1, wherein said movable portion is resiliently biased to said position.
 6. The intradermal delivery device of claim 5, wherein said indicating member comprises an expandable resilient member expandable from said position, the resilience of said expandable resilient member biasing said movable portion to said position.
 7. The intradermal delivery device of claim 6, wherein said expandable member is expandable by introducing a substance into said cavity under pressure.
 8. The intradermal delivery device of claim 6, wherein said expandable resilient member is integrally formed with said housing.
 9. The intradermal delivery device of claim 8, wherein said expandable resilient member is made from an elastomeric material.
 10. The intradermal delivery device of claim 9, wherein said housing includes a top wall and said top wall includes an opening and wherein said expandable resilient member closes said opening.
 11. The intradermal delivery device of claim 6, wherein the expandable resilient member is a diaphragm.
 12. The intradermal delivery device of claim 11, wherein said diaphragm is made from an elastomeric material.
 13. The intradermal delivery device of claim 6, wherein the expandable resilient member comprises at least a portion of the internal cavity dimensioned to receive a substance for delivery to a patient.
 14. The intradermal delivery device of claim 13, wherein said housing has a substantially non-expanding portion made from a substantially non-expanding material.
 15. The intradermal delivery device of claim 14, wherein said substantially non-expanding portion comprises an inlet for supplying said substance to said cavity.
 16. The intradermal delivery device of claim 15, further comprising a check valve connected to said inlet to prevent the substance from leaving the cavity through said inlet. 